Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in Caco-2 monolayers.
OBJECTIVE
The effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on heparin intestinal absorption were studied using rat in situ ileal and colonic instillations and Caco-2 monolayers.


METHODS
The flux of heparin was tested in the following groups: i) heparin alone, ii) heparin in the presence of SNAC, iii) heparin in the presence of propylene glycol (PG), and iv) heparin in the presence of SNAC and PG. Heparin absorption was measured by the APTT assay in the in situ models and by the anti-Factor Xa assay in Caco-2. SNAC and [3H]-SNAC fluxes were assessed by HPLC and by scintillation counting respectively.


RESULTS
In the rat ileal and colonic in situ instillations SNAC (17-35 mg) promoted heparin absorption in the presence and absence of PG without damaging the tissue. PG alone did not alter heparin absorption in situ, but it amplified the effect of SNAC. In Caco-2, enhanced heparin fluxes were variable in the presence of non-cytotoxic concentrations of SNAC (< 10 mg/ml) and these effects could not be discriminated from those of PG. Papp values for SNAC alone were 2.2 x 10(-5) cm/s and 2.0 x 10(-5) cm/s in the mucosal-to-serosal and serosal-to-mucosal directions respectively, suggesting a substantial passive transcellular flux. Transport of SNAC was significantly reduced in the presence of heparin and/or PG, perhaps indicating physical association between the agents.


CONCLUSIONS
SNAC augmented heparin absorption alone and in combination with PG in the rat in situ models without causing toxicity. Caco-2 had limitations for testing increased heparin absorption due to cytotoxic effects of high concentrations of SNAC and PG. However, SNAC itself was well absorbed across Caco-2 and its mechanism of permeation was determined.
Brayden
D
D
Elan Pharmaceutical Technologies, Trinity College, Dublin, Ireland. braydavi@iol.ie
Creed
E
E
O'Connell
A
A
Leipold
H
H
Agarwal
R
R
Leone-Bay
A
A
D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects / Q000648:ultrastructure; D002210:Caprylates / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival; D003106:Colon / Q000378:metabolism*; D005260:Female; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D010314:Partial Thromboplastin Time; D019946:Propylene Glycol / Q000494:pharmacology; D051381:Rats
D002210:Caprylates; C111140:N-(8-(2-hydroxybenzoyl)amino)caprylate; D019946:Propylene Glycol; D006493:Heparin